Structure-based design, synthesis, X-ray studies, and biological evaluation of novel HIV-1 protease inhibitors containing isophthalamide-derived P2-ligands

Arun K. Ghosh, Jun Takayama, Luke A. Kassekert, Jean Rene Ella-Menye, Sofiya Yashchuk, Johnson Agniswamy, Yuan Fang Wang, Manabu Aoki, Masayuki Amano, Irene T. Weber, Hiroaki Mitsuya

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


We describe the design, synthesis and biological evaluation of a series of novel HIV-1 protease inhibitors bearing isophthalamide derivatives as the P2-P3 ligands. We have investigated a range of acyclic and heterocyclic amides as the extended P2-P3 ligands. These inhibitors displayed good to excellent HIV-1 protease inhibitory activity. Also, a number of inhibitors showed very good antiviral activity in MT cells. Compound 5n has shown an enzyme Ki of 0.17 nM and antiviral IC50 of 14 nM. An X-ray crystal structure of inhibitor 5o-bound to HIV-1 protease was determined at 1.11 Å resolution. This structure revealed important molecular insight into the inhibitor-HIV-1 protease interactions in the active site.

Original languageEnglish (US)
Pages (from-to)4903-4909
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Issue number21
StatePublished - Nov 1 2015

Bibliographical note

Funding Information:
This research was supported by the National Institutes of Health (Grant GM53386 , A.K.G. and Grant GM62920 , I.T.W.). X-ray data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) beamline 22BM at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the U.S. Department of Energy , Basic Energy Sciences , Office of Science , under Contract No. W-31-109-Eng-38 . This work was also supported by the Intramural Research Program of the Center for Cancer Research , National Cancer Institute , National Institutes of Health , and in part by a Grant-in-Aid for Scientific Research (Priority Areas) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu Kagakusho), a Grant for Promotion of AIDS Research from the Ministry of Health, Welfare, and Labor of Japan , and the Grant to the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases (Renkei Jigyo) of Monbu-Kagakusho. The authors would like to thank the Purdue University Center for Cancer Research, which supports the shared NMR and mass spectrometry facilities.

Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.


  • Antiviral
  • Design
  • HIV-1 protease
  • Inhibitors
  • Isophthalamide
  • Synthesis

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